Severe hemolysis during primaquine radical cure of Plasmodium vivax malaria: two systematic reviews and individual patient data descriptive analyses

Primaquine (PQ) kills Plasmodium vivax hypnozoites but can cause severe hemolysis in patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency. We conducted two systematic reviews. The first used data from clinical trials to determine the variety of definitions and frequency of hematological serious adverse events (SAEs) related to PQ treatment of vivax malaria. The second used data from prospective studies and case reports to describe the clinical presentation, management, and outcome of severe PQ-associated hemolysis necessitating hospitalization. In the first review, SAEs were reported in 70 of 249 clinical trials. There were 34 hematological SAEs among 9,824 patients with P. vivax malaria treated with PQ, nine of which necessitated hospitalization or blood transfusion. Criteria used to define SAEs were diverse. In the second review, 21 of 8,487 articles screened reported 163 patients hospitalized after PQ radical cure; 79.9% of whom (123 of 154) were prescribed PQ at ≥ 0.5 mg/kg/day. Overall, 101 patients were categorized as having probable or possible severe PQ-associated hemolysis, 96.8% of whom were G6PD deficient (< 30% activity). The first symptoms of hemolysis were reported primarily on day 2 or 3 (45.5%), and all patients were hospitalized within 7 days of PQ commencement. A total of 57.9% of patients (77 of 133) had blood transfusion. Seven patients (6.9%) with probable or possible hemolysis died. Even when G6PD testing is available, enhanced monitoring for hemolysis is warranted after PQ treatment. Clinical review within the first 5 days of treatment may facilitate early detection and management of hemolysis. More robust definitions of severe PQ-associated hemolysis are required

Alternative transmission routes in the malaria elimination era: an overview of transfusion-transmitted malaria in the Americas

Submitted by Janaína Nascimento ([email protected]) on 2019-02-21T11:59:00Z No. of bitstreams: 1 ve_Alho_Regina_etal_INI_2017.pdf: 1190158 bytes, checksum: 8937322faefa31c89eb1bbd2f7d134a3 (MD5)Approved for entry into archive by Janaína Nascimento ([email protected]) on 2019-02-25T11:34:33Z (GMT) No. of bitstreams: 1 ve_Alho_Regina_etal_INI_2017.pdf: 1190158 bytes, checksum: 8937322faefa31c89eb1bbd2f7d134a3 (MD5)Made available in DSpace on 2019-02-25T11:34:33Z (GMT). No. of bitstreams: 1 ve_Alho_Regina_etal_INI_2017.pdf: 1190158 bytes, checksum: 8937322faefa31c89eb1bbd2f7d134a3 (MD5) Previous issue date: 2017Universidade do Estado do Amazonas. Manaus, AM, Brasil / Fundação de Hematologia e Hemoterapia do Amazonas. Manaus, AM, Brasil.Fundação de Medicina Tropical Dr. Heitor Vieira Dourado. Manaus, AM, Brasil.Universidade do Estado do Amazonas. Manaus, AM, Brasil / Fundação de Medicina Tropical Dr. Heitor Vieira Dourado. Manaus, AM, Brasil.Fundação de Hematologia e Hemoterapia do Amazonas. Manaus, AM, Brasil.Universidade do Estado do Amazonas. Manaus, AM, Brasil.Universidade do Estado do Amazonas. Manaus, AM, Brasil / Fundação de Medicina Tropical Dr. Heitor Vieira Dourado. Manaus, AM, Brasil.Sem afiliação.Fundação Oswaldo Cruz. Instituto Nacional de Infectologia Evandro Chagas. Rio de Janeiro, RJ, Brasil / Fundação Oswaldo Cruz. Instituto de Pesquisas Leônidas e Maria Deane. Manaus, AM, Brasil.Universidade do Estado do Amazonas. Manaus, AM, Brasil / Fundação de Medicina Tropical Dr. Heitor Vieira Dourado. Manaus, AM, Brasil.Universidade do Estado do Amazonas. Manaus, AM, Brasil / Fundação de Medicina Tropical Dr. Heitor Vieira Dourado. Manaus, AM, Brasil / Fundação Oswaldo Cruz. Instituto de Pesquisas Leônidas e Maria Deane. Manaus, AM, Brasil.Background: Transfusion-transmitted (TT) malaria is an alternative infection route that has gained little attention from authorities, despite representing a life-threatening condition. There has been no systematic review of this health problem in American countries. The aim of this study was to describe the clinical and epidemiological characteristics of TT malaria in the Americas and identify factors associated with lethality based on the studies published in the literature. Methods: Potentially relevant papers in all languages were retrieved from MEDLINE and LILACS. Additional articles were obtained from reviews and original papers. Publications on screening of candidate blood donors and on surveillance of TT malaria cases were included. Odds ratios with respective 95% confidence intervals (95% CI) were calculated. Epidemiological characteristics of blood donors of TT malaria cases, including a pooled positivity of different tests for malaria diagnosis, were retrieved. Results: A total of 63 publications regarding TT malaria from seven countries were included, from 1971 to 2016. A total of 422 cases of TT malaria were recorded. Most TT malaria cases were in females (62.0%) and 39.5% were in the ≥61 years-old age group. About half of all cases were from Mexico (50.7%), 40.3% from the United States of America (USA) and 6.6% from Brazil. Gyneco-obstetrical conditions (67.3%), surgical procedures (20.6%) and complications from neoplasias (6.1%) were the most common indications of transfusion. Packed red blood cells (RBCs) (50.7%) and whole blood (43.3%) were the blood products mostly associated with TT malaria. Cases were mostly caused by Plasmodium malariae (58.4%), followed by Plasmodium vivax (20.7%) and Plasmodium falciparum (17.9%). A total of 66.6% of cases were diagnosed by microscopy. Incubation period of 2–3 weeks was the most commonly observed (28.6%). Lethality was seen in 5.3% of cases and was associated with living in non-endemic countries, P. falciparum infection and concomitant neoplastic diseases. Conclusion: There is an important research and knowledge gap regarding the TT malaria burden in Latin American countries where malaria remains endemic. No screening method that is practical, affordable and suitably sensitive is available at blood banks in Latin American countries, where infections with low parasitaemia contribute greatly to transmission. Lethality from TT malaria was not negligible. TT malaria needs to be acknowledged and addressed in areas moving toward elimination

Utility of ultra-sensitive qPCR to detect Plasmodium falciparum and Plasmodium vivax infections under different transmission intensities

Background: The use of molecular diagnostics has revealed an unexpectedly large number of asymptomatic low-density malaria infections in many malaria endemic areas. This study compared the gains in parasite prevalence obtained by the use of ultra-sensitive (us)-qPCR as compared to standard qPCR in cross-sectional surveys conducted in Thailand, Brazil and Papua New Guinea (PNG). The compared assays differed in the copy number of qPCR targets in the parasite genome. Methods: Plasmodium falciparum (Pf) and Plasmodium vivax (Pv) parasites were quantified by qPCR amplifying the low-copy Pf_ and Pv_18S rRNA genes or the multi-copy targets Pf_varATS and Pv_mtCOX1. Cross-sectional surveys at the three study sites included 2252 participants of all ages and represented different transmission intensities. Results: In the two low-transmission areas, P. falciparum positivity was 1.3% (10/773) (Thailand) and 0.8% (5/651) (Bra- zil) using standard Pf_18S rRNA qPCR. In these two countries, P. falciparum positivity by Pf_varATS us-qPCR increased to 1.9% (15/773) and 1.7% (11/651). In PNG, an area with moderate transmission intensity, P. falciparum positivity significantly increased from 8.6% (71/828) by standard qPCR to 12.2% (101/828) by us-qPCR. The proportions of P. falciparum infections not detected by standard qPCR were 33%, 55% and 30% in Thailand, Brazil and PNG. Plasmodium vivax was the predominating species in Thailand and Brazil, with 3.9% (30/773) and 4.9% (32/651) positivity by Pv_18S rRNA qPCR. In PNG, P. vivax positivity was similar to P. falciparum, at 8.0% (66/828). Use of Pv_mtCOX1 us-qPCR led to a significant increase in positivity to 5.1% (39/773), 6.4% (42/651) and 11.5% (95/828) in Thailand, Brazil, and PNG. The proportions of P. vivax infections missed by standard qPCR were similar at all three sites, with 23%, 24% and 31% in Thailand, Brazil and PNG. Conclusion: The proportional gains in the detection of P. falciparum and P. vivax infections by ultra-sensitive diag- nostic assays were substantial at all three study sites. Thus, us-qPCR yields more precise prevalence estimates for both P. falciparum and P. vivax at all studied levels of endemicity and represents a significant diagnostic improvement

Morphological and Transcriptional Changes in Human Bone Marrow During Natural Plasmodium vivax Malaria Infections.

--- - Label: BACKGROUND NlmCategory: BACKGROUND content: The presence of Plasmodium vivax malaria parasites in the human bone marrow (BM) is still controversial. However, recent data from a clinical case and experimental infections in splenectomized nonhuman primates unequivocally demonstrated the presence of parasites in this tissue. - Label: METHODS NlmCategory: METHODS content: In the current study, we analyzed BM aspirates of 7 patients during the acute attack and 42 days after drug treatment. RNA extracted from CD71+ cell suspensions was used for sequencing and transcriptomic analysis. - Label: RESULTS NlmCategory: RESULTS content: We demonstrated the presence of parasites in all patients during acute infections. To provide further insights, we purified CD71+ BM cells and demonstrated dyserythropoiesis and inefficient erythropoiesis in all patients. In addition, RNA sequencing from 3 patients showed that genes related to erythroid maturation were down-regulated during acute infections, whereas immune response genes were up-regulated. - Label: CONCLUSIONS NlmCategory: CONCLUSIONS content: This study thus shows that during P. vivax infections, parasites are always present in the BM and that such infections induced dyserythropoiesis and ineffective erythropoiesis. Moreover, infections induce transcriptional changes associated with such altered erythropoietic response, thus highlighting the importance of this hidden niche during natural infections

Priority use cases for antibody-detecting assays of recent malaria exposure as tools to achieve and sustain malaria elimination

Measurement of malaria specific antibody responses represents a practical and informative method for malaria control programs to assess recent exposure to infection. Technical advances in recombinant antigen production, serological screening platforms, and analytical methods have enabled the identification of several target antigens for laboratory based and point-of-contact tests. Questions remain as to how these serological assays can best be integrated into malaria surveillance activities to inform programmatic decision-making. This report synthesizes discussions from a convening at Institut Pasteur in Paris in June 2017 aimed at defining practical and informative use cases for serology applications and highlights five programmatic uses for serological assays including: documenting the absence of transmission; stratification of transmission; measuring the effect of interventions; informing a decentralized immediate response; and testing and treating P. vivax hypnozoite carriers

Experimental Plasmodium vivax infection of key Anopheles species from the Brazilian Amazon

Made available in DSpace on 2015-09-21T17:25:38Z (GMT). No. of bitstreams: 2 license.txt: 1914 bytes, checksum: 7d48279ffeed55da8dfe2f8e81f3b81f (MD5) jose_lima_etal_IOC_2013.pdf: 530553 bytes, checksum: ecc989c032bd9da39e398d263e88b3ae (MD5) Previous issue date: 2013Fundação Oswaldo Cruz. Instituto Leônidas e Maria Deane. Manaus, AM, Brasil / Fundação Oswaldo Cruz. Centro de Pesquisas René Rachou. Belo Horizonte, MG, Brasil.Fundação de Medicina Tropical Dr. Heitor Vieira Dourado. Manaus, AM, Brasil / Universidade do Estado do Amazonas. Manaus, AM, Brasil.Instituto Nacional de Pesquisas da Amazônia, Manaus, AM, Brasil / Universidade do Estado do Amazonas. Manaus, AM, Brasil. / Ministerio da Saúde. Núcleo Amazonas. Fundação de Vigilância em Saúde. Manaus, AM, Brasil.Universidade Federal de Mato Grosso. Cuiabá, MT, Brasil.Instituto Nacional de Pesquisas da Amazônia. Manaus, AM, Brasil.Fundação Oswaldo Cruz. Instituto Leônidas e Maria Deane. Manaus, AM, Brasil.Fundação de Medicina Tropical Dr. Heitor Vieira Dourado. Manaus, AM, Brasil / Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Rio de Janeiro, RJ, Brasil.Fundação de Medicina Tropical Dr. Heitor Vieira Dourado. Manaus, AM, Brasil / Universidade do Estado do Amazonas. Manaus, AM, Brasil.Fundação Oswaldo Cruz. Centro de Pesquisas René Rachou. Belo Horizonte, MG, Brasil.Fundação de Medicina Tropical Dr. Heitor Vieira Dourado. Manaus, AM, Brasil / Universidade do Estado do Amazonas. Manaus, AM, Brasil.Instituto Nacional de Pesquisas da Amazônia. Manaus, AM, Brasil.Fundação de Medicina Tropical Dr. Heitor Vieira Dourado. Manaus, AM, Brasil / Fundação Oswaldo Cruz. Centro de Pesquisas René Rachou; Belo Horizonte, MG, Brasil.Background: Anopheles darlingi is the major malaria vector in countries located in the Amazon region. Anopheles aquasalis and Anopheles albitarsis s.l. are also proven vectors in this region. Anopheles nuneztovari s.l. and Anopheles triannulatus s.l. were found infected with Plasmodium vivax; however, their status as vectors is not yet well defined. Knowledge of susceptibility of Amazon anopheline populations to Plasmodium infection is necessary to better understand their vector capacity. Laboratory colonization of An. darlingi, the main Amazon vector, has proven to be difficult and presently An. aquasalis is the only available autonomous colony. Methods: Larvae of An. darlingi, An. albitarsis s.l., An. nuneztovari s.l. and An. triannulatus s.l. were collected in the field and reared until adult stage. Adults of An. aquasalis were obtained from a well-established colony. Mosquitoes were blood-fed using a membrane-feeding device containing infected blood from malarial patients. The infection of the distinct Anopheles species was evaluated by the impact variance of the following parameters: (a) parasitaemia density; (b) blood serum inactivation of the infective bloodmeal; (c) influence of gametocyte number on infection rates and number of oocysts. The goal of this work was to compare the susceptibility to P. vivax of four field-collected Anopheles species with colonized An. aquasalis. Results: All Anopheles species tested were susceptible to P. vivax infection, nevertheless the proportion of infected mosquitoes and the infection intensity measured by oocyst number varied significantly among species. Inactivation of the blood serum prior to mosquito feeding increased infection rates in An. darlingi and An. triannulatus s.l., but was diminished in An. albitarsis s.l. and An. aquasalis. There was a positive correlation between gametocyte density and the infection rate in all tests (Z = −8.37; p < 0.001) but varied among the mosquito species. Anopheles albitarsis s.l., An. aquasalis and An. nuneztovari s.l. had higher infection rates than An. darlingi. Conclusion: All field-collected Anopheles species, as well as colonized An. aquasalis are susceptible to experimental P. vivax infections by membrane feeding assays. Anopheles darlingi, An. albitarsis s.l. and An. aquasalis are very susceptible to P. vivax infection. However, colonized An. aquasalis mosquitoes showed the higher infection intensity represented by infection rate and oocyst numbers. This study is the first to characterize experimental development of Plasmodium infections in Amazon Anopheles vectors and also to endorse that P. vivax infection of colonized An. aquasalis is a feasible laboratory model

High prevalence and mortality due to Histoplasma capsulatum in the Brazilian Amazon: An autopsy study

Background: Histoplasmosis is acquired by inhalation of spores of the dimorphic fungus Histoplasma spp. Although this pathogen is distributed worldwide, it is more prevalent in the Americas. However, the real burden of histoplasmosis remains undefined in many endemic regions. Methodology: We conducted a series of 61 autopsies to individuals who died in a hospital in the Brazilian Amazon focused on infectious diseases. We performed a detailed histological and microbiological evaluation with genetic characterization of Histoplasma strains with the aim to evaluate the contribution of histoplasmosis to morbidity and mortality. Additionally, we assessed the clinicopathological correlation. Principal findings: Evidence of Histoplasma infection was detected in 21 patients (34%). Eight cases were disseminated infections, all of them occurred in HIV-positive patients. Six cases were localized histoplasmosis, limited to the lungs. In seven patients Histoplasma DNA was detected by PCR in patients with no histological lesions. Histoplasma infection was detected in 38% of HIV-positive patients and was a major contributor to death in 22% of them. Lungs, liver and spleen were affected in all cases of disseminated histoplasmosis. Phylogenetic analysis of the strains suggested a high diversity of Histoplasma species circulating in the Brazilian Amazon. Histoplasmosis was clinically missed in 75% of the disseminated infections. Conclusions: The high incidence of histoplasmosis, the low index of clinical suspicion, and the severity of the disseminated disease highlight the need of proactively implementing sensitive routine screening methods for this pathogen in endemic areas. Antifungal prophylaxis against Histoplasma should be encouraged in the severely immunocompromised HIV patients in these areas. In conclusion, substantial mortality is associated with disseminated histoplasmosis among HIV-positive patients in the Brazilian Amazon